Indian J Pediatr DOI 10.1007/s12098-016-2040-3
Chronic Granulomatous Disease Amit Rawat 1 & Sagar Bhattad 1 & Surjit Singh 1
Received: 24 November 2015 / Accepted: 13 January 2016 # Dr. K C Chaudhuri Foundation 2016
Abstract Chronic granulomatous disease (CGD) is the most common symptomatic phagocytic defect. It is caused by mutations in genes encoding protein subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD is characterized by a defective intracellular killing of phagocytosed organisms due to a defective oxidative burst in the neutrophils and macrophages. It is inherited in either X-linked recessive or autosomal recessive pattern. Staphylococcus aureus and Aspergillus species are the most common organisms reported. Infections with Burkholderia, Serratia, and Nocardia warrant a screen for CGD. Suppurative lymphadenitis, cutaneous abscesses, pneumonia and diarrhea constitute the most common problems in children with CGD. A small percentage of children develop autoimmune manifestations (e.g., rheumatoid arthritis, systemic lupus erythematosus, colitis, autoimmune hepatitis) and warrant immunosuppression. X-linked carriers of CGD are at an increased risk of developing autoimmune diseases. Nitrobluetetrazolium dye reduction test and dihydro-rhodamine assay by flow cytometry are the screening tests for this disorder. While most children do well on long term antibiotic and antifungal prophylaxis, those with severe forms warrant hematopoietic stem cell transplant. The role of regular interferon-γ injections is debatable. Evidence for white cell transfusions is sparse, and gene therapy is under trial.
* Amit Rawat [email protected]
Pediatric Allergy and Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
This current review highlights various aspects and studies in CGD. X-linked form of CGD has been noted to carry a poorer prognosis compared to autosomal recessive variants. However, recent evidence suggests that outcome in CGD is determined by the amount of residual NADPH oxidase activity irrespective of mode of inheritance. Keywords Chronic granulomatous disease . NADPH oxidase complex . CYBB gene . NCF1 gene . NCF2 gene . Dihydrorhodamine assay
Introduction Chronic granulomatous disease (CGD) is a rare primary immunodeficiency affecting 1 in 250,000 individuals . It is characterized by a defective intracellular killing of phagocytosed organisms. CGD is caused by mutations in genes encoding protein subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which plays a pivotal role in the respiratory burst in leukocytes. Respiratory burst results in the production of oxygen free radicals like superoxide ion (O2-), hydrogen peroxide (H2O2), hypochlorite ion (HOCl) and hydroxyl radical (OH-). These oxygen free radicals are required for killing of phagocytosed intracellular pathogens. As a result of defective NADPH oxidase system, children with CGD are predisposed to recurrent and recalcitrant bacterial and fungal infections . The American and European cohorts of 368 and 429 patients respectively are the largest groups of CGD reported to date. These cohorts provide useful insight into the clinical manifestations and outcome of CGD [1, 3]. Long-term antibiotic and antifungal prophylaxis, interferon gamma (IFN-γ) therapy, hematopoietic stem cell transplant (HSCT) and gene therapy are the various forms of therapies studied in CGD. The
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outcome in CGD is difficult to predict. While those with severe disease succumb in infancy, children with milder forms survive into adulthood on antimicrobial prophylaxis. Thus, deciding the best form of therapy for a given patient may be challenging and treatment needs to be tailored based on the severity of the disease.
Historical Perspective Janeway and colleagues published the first report of a probable case of CGD in which they described a child with recurrent infections with hypergammaglobulinemia . Landing et al. subsequently described a patient with recurrent infections and infiltration of viscera with lipid-laden histiocytes . In 1959, Bridges and Good reported a granulomatous disorder in boys which was almost always fatal and described this as a “new syndrome” . It was the first time that the disease had been characterized as a distinct syndrome and was also known as “Bridges-Good syndrome”. Bernard Babior linked the defect of superoxide production of white blood cells to the etiology of the disease . Demonstration of defective reduction of nitroblue tetrazolium (NBT) dye by phagocytes in CGD patients was an important landmark in the history of CGD  as this provided a laboratory test for diagnosis of CGD. The NBT dye reduction test has been in use for decades until recently when it was replaced with flow cytometric based test for the oxidative burst. Gene localization for X-linked recessive chronic granulomatous diseases (X-CGD) was reported in 1986 [9, 10] and this was followed by discovery of defects in other components of the NADPH oxidase complex like p22 phox , p67phox  and p47phox .
Genetics of Chronic Granulomatous Disease Chronic granulomatous disease is inherited as an X-linked recessive (X-CGD) or autosomal recessive disorder (ARCGD). Worldwide, X-CGD is more prevalent (65–70 %) [1, 3, 13, 14]. However, AR-CGD is reported as the most common form of CGD in parts of the world with high rates of consanguinity [15, 16]. AR-CGD was reported to be more frequent than X-CGD in an Indian cohort of 17 children with CGD . NADPH oxidase complex is composed of five major subunits. Two of these – gp91phox and p22phox are membrane bound components encoded by the CYBB gene and the CYBA gene respectively. The remaining three components of the complex include p47phox, p67phox and p40phox encoded by the corresponding genes namely, NCF1 (neutrophil cytosolic factor 1), NCF2 (neutrophil cytosolic factor 2) and NCF4 (neutrophil cytosolic factor 4). Mutations in the
gp91phox gene (CYBB on chromosome Xp21.1) cause the X-linked recessive form of the disease while the rest are inherited in an autosomal recessive pattern (Table 1). Relative frequencies of the various genetic forms in different cohorts have been tabulated (Table 2). For complete NADPH oxidase function, a GTPase known as Rac2 is also required . A dominant-negative mutation was recognized in the hematopoietic-specific Rac2 GTPase, in an infant who had a predisposition to bacterial infections similar to CGD and leukocyte adhesion deficiency .
Clinical Manifestations Usual Manifestations The most commonly implicated bacteria causing infections in CGD include Staphylococcus aureus and the Gram-negative Enterobacteriaceae. The latter group includes Salmonella, Aerobacter, Klebsiella, and Serratia. Pseudomonas (Burkholderia cepacia), Actinomyces, and Nocardia are other important pathogens in CGD. One must keep in mind a possibility of CGD while working up patients with nocardiosis. Compared to non-CGD patients, children with CGD do not have an additional risk for infections with catalase negative bacteria. Pneumonia, suppurative lymphadenitis, cutaneous abscess, liver abscess and gut infections are the common infections reported. Other manifestations include failure to thrive and inflammatory complications. Granulomatous inflammation can result in obstructive symptoms. While the majority of patients with CGD present with recurrent infections from early childhood, a small proportion may present in adulthood. This delay in the presentation is attributed to the residual NADPH oxidase function in these patients. In the American cohort, pneumonia was noted in 79 %, suppurative lymphadenitis in 53 % while subcutaneous abscesses in 52 % . In the European cohort, pneumonia/lung abscess was noted in 66 %, cutaneous infections in 53 %, lymphadenitis in 50 % and gastrointestinal involvement in 48 % . In the Indian cohort of 17 patients, pneumonia and lymphadenitis were noted in 82 %, cutaneous infections in 47 % and hepatic abscesses occurred in 23 % . Infections that were less commonly reported in these series include osteomyelitis, brain abscess, eye infections and urinary tract infections. A small subset were noted to have autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis and autoimmune cytopenia in the European cohort . In the European study, Staphylococcus aureus, Aspergillus species, and Salmonella species were the most common pathogens identified, while Pseudomonas species
Indian J Pediatr Table 1 Genes involved in CGD and related genes
No. of exons
Mode of inheritance
CYBB CYBA NCF1 NCF2 RAC2 (related gene) G6PD (related gene)
gp91phox p22phox p47phox p67phox Rac2 G6PD
Xp21.1 16q24 7q11.23 1q25
30 kb 8.5 kb 15 kb 40 kb
13 6 11 16
X-linked recessive Autosomal recessive Autosomal recessive Autosomal recessive
18 kb 18 kb
Autosomal recessive X-linked recessive
and Burkholderia cepacia were rarely observed . Aspergillus species was the leading cause of infection in the American cohort (41 %) followed by Staphylococcus aureus (12 %), Burkholderia (8 %), Nocardia (7 %) and Mycobacteria (4 %). Serratia and Candida were uncommon . In contrast, Candida was very commonly reported from the Indian cohort . Certain infections like Nocardia, Serratia, and Chromobacterium violaceum, although rare are strong pointers towards an underlying immune deficiency, especially CGD in the appropriate clinical setting. Children with CGD are also predisposed to tuberculosis and atypical mycobacterial infections . Increased risk of adverse reactions to BCG vaccine is noted, and this has been recently reported in up to 30 % of patients with CGD in Latin America . It must be emphasized that concerted efforts may be required to determine a particular etiological agent in patients with CGD as cultures performed routinely may be sterile in the majority. CGD portends an increased risk of invasive fungal infections compared to other primary immunodeficiencies. Patients with CGD have a 20–40 % life time incidence of fungal infections. Aspergillus species are the most common fungal infections in CGD [1, 3]. Aspergillus nidulans complex has been almost exclusively found in CGD patients. But other unusual fungi also occur, including Paecilomyces species. It Table 2
is indeed interesting to note that the dimorphic fungi like Histoplasma, Coccidioides, and Blastomyces have seldom being reported in patients with CGD. Aspergillus species cause pneumonia and spread contiguously to pleura, ribs and vertebra. Angioinvasion is uncommon.
Autoimmunity and Inflammatory Complications Children with CGD are predisposed to autoimmune and inflammatory complications. These complications were noted in about 6 % of children in the European cohort. Discoid lupus was the most common manifestation. Other diseases noted were rheumatoid arthritis, systemic lupus erythematosus (SLE), dermatomyositis, sacroiliitis, idiopathic thrombocytopenia and autoimmune hepatitis . In the National Institute of Health (NIH) cohort of 250 patients, 5 % had inflammatory complications . Children with inflammatory granulomas may present with intestinal or ureteric obstruction. A significant proportion of children in the American cohort were reported to have gastric, and ureteric outlet obstruction and these were more common in X-CGD compared to the AR-CGD. Other inflammatory complications include colitis/enteritis that was noted in 17 % and 9 % of CGD patients in the American
Relative frequencies of different forms of CGD in previously reported cohorts of CGD
Total no. of XR (gp91phox) AR p47phox p67phox p40phox P22phox patients
Winkelstein et al.  El Kares et al.  Martire et al.  van den Berg et al.  Koker et al.  Rawat et al.  Bortoletto et al.  de Oliveira-Junior et al. 
United States of America Tunisia Italy Europe Turkey India (Single centre) United States of America (Single centre) Latin America
368 15 60 @ 429 89$ 17 27$$ 71
259 0 39 290 34 7** 19 53
81 15 6 139 50 10 8 18
45 5 5 69 17 7 2 16
10 5 0 11 13 NA 2 0
NA * NA# 0 NA ## 0 NA NA 0
7 3 1 22 20 NA NA 2
NA Information not available, *19 were reported as unknown, # 2 were reported as unknown, ## 37 were reported as unknown, $ 5/89 patients – inheritance not determined, @ 25/60 patients – inheritance not determined, $$ 11/27 were genotyped, ** genetic analysis was performed in 13/17 and in these 6 had mutations in CYBB, while 7 had mutations in NCF1
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and European cohort respectively [1, 3]. Children presenting with colitis may be misdiagnosed as inflammatory bowel disease (IBD) , however, presence of atypical infections and young age at onset of gastrointestinal symptoms should make one suspect CGD in a child with presumed IBD. In a study of 140 patients with CGD, 32 % were noted to have gastrointestinal involvement and this was significantly more frequent in X-CGD , however, presence/absence of gastrointestinal involvement did not affect the mortality of patients in this cohort. Hemophagocytic lymphohistiocytosis (HLH) is a rare complication of CGD, and this has been reported only as case reports so far [17, 25–27]. CGD is associated with hyperinflammation and a proinflammatory cytokine milieu that predisposes these children to HLH. Most cases of HLH in children with CGD are secondary to infections, mainly with Burkholderia cepacia and Leishmania. Increased risk of non-infectious complications like diabetes mellitus has been reported in p47phox deficient AR-CGD. In a study comprising 64 p47phox deficient CGD patients being followed at NIH, 9.4 % developed diabetes mellitus while none amongst 165 of X-CGD had this complication . Patients with CGD have been noted to have significant elevations in traditional cardiovascular risk factors like hypertension and inflammatory markers. Abnormalities in the lipid profile have been described, notably high-sensitivity C-reactive protein, oxidized low-density lipoprotein, and low highdensity lipoprotein. Despite this, a low prevalence of atherosclerosis has been noted in patients with CGD. Thus, it is likely that NADPH oxidase may be inherently involved in the pathogenesis of atherosclerosis .
Clinical Manifestations in X-Linked Carriers of CGD X-linked carrier females of CGD are known to suffer from autoimmune disorders. SLE and other autoimmune diseases are well known in carriers of X-linked CGD. Recurrent aphthous ulcers, Raynaud phenomenon, and polyarthritis have all been reported [30–33]. Compared to healthy population, these features are significantly more common in X-linked carriers. A review summarizing the clinical manifestations of X-linked carriers has been recently published by Battersby et al. .
Diagnosis Diagnosis of CGD is based on the demonstration of an absent respiratory burst. When phagocytes in healthy controls are stimulated, they produce superoxide as a result of NADPH oxidase activation. On the contrary, when phagocytes from CGD patients
are stimulated, they fail to generate superoxide. X-linked carriers have two populations of cells; one group of cells are capable of producing a respiratory burst and thereby produce superoxide and a second group of cells which cannot do so. Diagnosis of CGD can be made by either by the Nitroblue Tetrazolium (NBT) dye reduction test or by using flow cytometry based Dihydrorhodamine (DHR) assay. X-linked carrier status can also be detected by DHR test. NBT Reduction Test Baehner and Nathan in 1967 demonstrated that leukocytes in patients with CGD failed to reduce NBT dye due to defective oxidase and hence they were unable to utilize oxygen and produce reactive species . For decades, this test has been used as a screening test for the diagnosis of CGD. NBT is a yellow dye. On reduction, it forms blue formazan. This change is observed and quantified under a microscope. The phagocytes from CGD patients fail to reduce NBT and thus remain yellow. Normal phagocytes reduce the dye and produce the blue precipitate of formazan. X-linked carriers would demonstrate both colors as two populations of cells are present. One must note that the reporting of this test is subjective and would require some expertise. Demonstration of two distinct populations of cells as in the case of X-linked carriers may be challenging . Today this test has been replaced with an objective test that utilizes flow cytometry – the DHR test. Dihydrorhodamine (DHR) Test Dihydrorhodamine dye reduction test is a flow cytometric based test. Neutrophils are stimulated with Phorbol-12Myristate-13 Acetate (PMA) to produce reactive oxygen species such as hydrogen peroxide. These reactive species then react with a dye such as dihydrorhodamine (DHR) that is reduced to rhodamine which is fluorescent. This change in fluorescence is detected by the flow cytometer. In healthy subjects, an increase in fluorescence would result in a shift of the curve to the right in the histogram (Fig. 1). A failure to shift or a reduced shift is suggestive of an abnormal test. If a mosaic pattern is encountered with two populations of neutrophils, one showing fluorescence on stimulation and the other which does not, it is indicative of a carrier state for X-linked CGD. Thus, DHR test helps in making a reliable diagnosis of cases and carriers of X-linked. It may, however, be noted that carriers of autosomal recessive forms of CGD cannot be detected by DHR as one normal allele is sufficient for adequate function. Expression of protein subunits of NADPH oxidase on neutrophils can be studied by flow cytometry (Fig. 2), which may help in further classifying the type of CGD. Two other fluorescent probes namely 2′7′-dichlorofluorescein and 5,6-carboxy-2′7′- dichlorofluorescein diacetate may be used
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c Fig. 1 Dihydrorhodamine assay in (a) a normal healthy subject (b) an X-linked carrier of CGD due to defect in gp91 phox (CYBB) and (c) a patient with CGD (Unstimulated neutrophils left panel, stimulated neutrophils middle panel and overlay right panel)
instead of DHR to perform the same test. But DHR has been reported to be superior compared to these probes in bringing out the difference between normal and abnormal population of phagocytes  and is thus accepted worldwide as the screening test of choice for CGD.
suggests a defect in gp91phox and a mutation in the CYBB gene. Hence, the type of CGD may be determined even in the absence of genetic studies, although genetic studies would be required to confirm the diagnosis and for genetic counseling.
NADPH Oxidase Component Estimation
Treatment The subtypes of CGD may be determined by studying the expression of various subunits of NADPH oxidase complex by flow cytometry or Western blot. Monoclonal antibodies against the different subunits are commercially available. Flow cytometry based estimation of gp91phox/p22 phox using monoclonal antibody against b558 cannot differentiate defect due to gp91phox or p22phox in a patient showing decreased or absent staining. However, a mosaic pattern in the mother or sisters of the index patient with two populations of cells
Prevention of Infections General Health Care Reducing exposure to infectious agents and general hygiene measures form a cornerstone in improving overall outcome in children with CGD. All routine immunizations must be administered, except BCG. Exposure to hay, mulch, animal
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c Fig. 2 b558 (gp91phox/p22phox) expression in (a) normal healthy subject and (b) a carrier of X-linked CGD and (c) a patient with CGD (Neutrophils left panel, monocytes middle panel and overlay right panel)
stables, rotten plants, compost piles and construction sites should be avoided, thereby reducing the risk of aspergillosis.
frequency of major infections from one episode every year to one every 3.5 y in a study by Margolis et al. .
Antibiotic Prophylaxis Antifungal Prophylaxis The mainstay of clinical care in children with CGD is lifelong antibiotic and antifungal prophylaxis. Trimethoprim/ sulfamethoxazole (co-trimoxazole) is commonly employed for long-term prophylaxis. It is lipophilic and is active against majority of Gram-negative bacteria as well as Staphylococci, Serratia marcescens and Burkholderia. Although there are no randomized controlled trials to prove the efficacy of cotrimoxazole, several retrospective studies have supported its usage in children with CGD [37, 38]. Prophylactic trimethoprim/sulfamethoxazole (TMP-SX) reduced the
Itraconazole is the recommended prophylaxis for fungal infections. It is highly effective against Aspergillus species, which is an important pathogen in CGD. In a randomized, double-blind, placebo-controlled crossover study by Gallin et al. , 39 enrolled CGD patients had one severe fungal infection in the itraconazole group compared with seven cases in the placebo recipients. Thus, itraconazole is routinely used in patients with CGD.
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Interferon Gamma (IFNγ) Prophylaxis Experiments have shown an improvement in phagocyte function following IFNγ injections in-vitro. The efficacy and potential toxicity of IFNγ were evaluated in a cohort of 128 CGD patients in a multicenter, randomized, double-blind, placebocontrolled study . It demonstrated a clear benefit in terms of reduction in infections [IFN group – 14/63, placebo – 30/65 (p = 0.002)]. However, in an Italian multicenter, prospective controlled non-randomised study involving 60 patients, no change in infection rate was noted in CGD patients on IFNγ compared to controls (p = 0.07) . While most European physicians do not use IFNγ prophylaxis routinely in CGD, it is universally prescribed in the USA. Treatment of Acute Infections Antibiotics Unlike that in immune competent individuals, infections in CGD may take weeks to resolve. A prolonged course of antimicrobials is thus warranted. Early identification of infections and prompt initiation of parenteral antimicrobials remains the cornerstone of management. Until culture results are available, broad spectrum antimicrobials that provide coverage to Gram negative (Burkholderia, Serratia) and Gram positive organisms (Staphylococcus) must be initiated. In case of no response in 48 h, empirical antifungal agents (amphotericin/ voriconazole) may be added. Antifungals Injectable amphotericin may be initiated as an empirical initial antifungal treatment in patients with CGD. In case of invasive aspergillosis, voriconazole has been shown to be superior to conventional amphotericin B. Studies have demonstrated the safety of voriconazole in children with CGD. A response rate of up to 55 % has been shown in the difficult-to-treat CNS fungal infections . Thus, voriconazole is currently the drug of choice for invasive aspergillus infections in children with CGD. Fungal infections require prolonged treatment over several months. After the infection has been controlled, patients should be continued on prophylaxis with oral itraconazole or voriconazole to prevent recurrence or reactivation of infection, which is essentially continued for life. Surgery Children with CGD often require drainage of abscesses (cutaneous, lung and liver). Other surgical indications are obstructive complications like hydronephrosis and intestinal obstruction. The operative sites in CGD are at high risk of getting infected, and they heal gradually and may form fistulas.
Therefore, sutures in such cases should not be removed early and drains need to be left in place for a prolonged period . Postoperative management of these patients is challenging. Prolonged courses of post-operative antibiotics are warranted. White Cell Transfusions Adding a small number of normal neutrophils to CGD neutrophils in experimental models resulted in killing of extracellular Aspergillus hyphae . Thus it was hypothesized that white cell transfusions may have a role in management of CGD. These have been used in a few CGD patients for management of serious fungal and bacterial infections resistant to usual line of management . Albeit, no controlled trials have ever been performed demonstrating the role of white cell transfusions and hence their usage remains controversial. Thus, white cell transfusions currently find a limited role in the treatment of CGD. Treatment of Inflammatory Complications Children with CGD are predisposed to several inflammatory complications like gastric outlet obstruction, ureteral and urethral obstruction, inflammatory colitis, granulomatous cystitis, and inhalational acute miliary pneumonia. These warrant addition of low-dose steroids. They can be initiated at a dose of 1 mg/kg/d of oral steroids which is given for two weeks and is tapered over 4–6 wk. Using corticosteroids in patients with CGD is a tricky and challenging situation as it may result in unmasking of serious infections and thus, steroids must be used judiciously. Infliximab has also been used as a treatment modality in some patients with significant inflammatory complications, refractory to corticosteroid therapy. Curative Therapy Hematopoietic Stem Cell Transplant Hematopoietic stem cell transplant (HSCT) is increasingly being used in treatment of CGD and with experience, results are much better than before. This is now considered to be curative in selected CGD patients. Historically, the first bone marrow transplant was performed in CGD in 1973. Subsequently, a multicentric study from Europe reported the outcome of 27 CGD patients . Overall survival in this cohort was 85 %, with 81 % of patients cured of CGD. Survival in patients who did not have a prior infection at the time of transplantation was excellent. Kang et al. have recently reviewed the role of HSCT in CGD. As per the review, 99 transplants in CGD, excluding cord blood recipients, have been published until 2011 . Fifty transplants have occurred in the last ten years, compared to 49 in the prior 27 y; thereby indicating the growing
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interest in HSCT in the treatment of CGD. With the introduction of non-myeloablative regimens, the outcome has improved, and transplants can now be done with ongoing infections.
Contributions AR: Planning, editing and finalizing the manuscript; SB: Review of literature, writing the initial draft of the manuscript; SS: Editing, final approval of manuscript and will act as guarantor for the paper. Compliance with Ethical Standards Conflict of Interest None.
Gene Therapy Source of Funding None.
Several researchers are involved in gene therapy trials in CGD world over and this is an active field of research. It seems logical and feasible to perform such therapy in CGD patients as genes involved in NADPH oxidase are metabolic genes and are not involved in cellular proliferation. At present, gene therapy continues to be in an experimental phase .
In the American cohort, children with X-CGD had significantly higher rates of serious infections compared to AR-CGD. Mortality in X-CGD and AR-CGD was 21.2 % and 8.6 % respectively, and thus children with X-CGD had significantly higher mortality (p < 0.02) . In the European cohort, AR-CGD was diagnosed much later in life, and the mean survival time was significantly better in AR patients (49.6 y) than in X-CGD (37.8 y). Thus, AR-CGD was reported to have better outcome compared to the X-linked counterpart . There have been recent reports to suggest that prognosis in patients with CGD is primarily determined by the amount of residual NADPH oxidase activity irrespective of mode of inheritance  and this is influenced by the type of mutation rather than the gene that is affected in CGD. Thus, determining residual oxidase activity may guide the mode of therapy in a given patient. Overall, with early recognition of the disease, long term antimicrobial prophylaxis and the treatment of selected patients with HSCT, survival in CGD patients has improved over the years.
7. 8. 9.
Chronic granulomatous disease, although rare, is the most common symptomatic primary immune deficiency with a phagocytic defect. Children with CGD are predisposed to bacterial and fungal infections. DHR test is the screening tool of choice. Early recognition and prompt therapy have led to an overall increase in survival in CGD. While many patients do well on long term antibiotic and antifungal prophylaxis, a subset of them with severe manifestations warrant HSCT.
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